Biomedical subjects

W Weber

Publications and source records attributed to W Weber.

At least 127 records · Page 7Linked to original sources

PubMed1998

Psychiatric, neuropsychological, and psychosocial features of DSM-IV subtypes of attention-deficit/hyperactivity disorder: results from a clinically referred sample.

OBJECTIVE: To assess the validity of the DSM-IV subtypes of attention-deficit/hyperactivity disorder (ADHD). METHOD: Using structured diagnostic interviews and psychometric measures of cognitive and social functioning, the authors assessed 413 children and adolescents consecutively referred to a pediatric psychopharmacology clinic since 1991. RESULTS: Marked psychiatric differences were found among DSM-IV subtypes of ADHD, but few differences were found in cognitive or psychosocial functioning. The greatest psychiatric differences were found between the combined-type subjects (who tended to show more impairment in multiple domains) and the other two subgroups. The inattentive patients, however, were more likely to have required extra help in school. The hyperactive-impulsive patients were not different from controls on rates of depression, Child Behavior Checklist measures of social functioning, or psychometric measures of intellectual functioning and academic achievement. CONCLUSIONS: The results suggest that, regarding clinical features, combined-type patients have a more severe disorder than the other DSM-IV subtypes.

Adolescent↗

PubMed1998

Phenotypic differences in familial adenomatous polyposis based on APC gene mutation status.

BACKGROUND: Familial adenomatous polyposis (FAP) is a clinically well defined hereditary disease caused by germline mutations within the adenomatous polyposis coli (APC) gene. Although several techniques are applied in the mutation analysis of FAP kindreds about 20-50% of cases remain unclear, with no APC mutation identified (APC negative). AIMS: To delineate phenotypic differences between APC positive and APC negative patients with respect to colonic and extracolonic disease in order to determine whether additional mechanisms are involved in the pathogenesis of FAP. METHODS: The entire coding region of the APC gene was analysed using single stranded conformation polymorphism and protein truncation tests in 50 Swiss FAP families with a total of 161 affected individuals. Differences in phenotypic manifestation were statistically evaluated by Student's t test, Fisher's exact test, and chi2 test. RESULTS: Thirty six families (72%) were APC positive. Statistically significant differences between APC positive and APC negative groups were found for the mean age at diagnosis of colonic polyposis (35.2 versus 45.3 years, respectively) and for the occurrence of stomach polyps (14 patients, all APC positive). Additionally, APC negative patients displayed lower polyp numbers at diagnosis and less extracolonic manifestations. CONCLUSIONS: FAP kindreds without detected APC gene mutations present with a notably milder disease phenotype compared with APC positive families, suggesting that different genetic factors might be involved.

Adenomatous Polyposis Coli↗

PubMed1998

[The effect of food on theophylline absorption].

The possible influence of the food and fat content of meals on the bioavailability and pharmacokinetics of a 350 mg sustained release theophylline (CAS 58-55-9) preparation (Bronchoretard) was investigated after single dose oral administration to 18 volunteers in a randomised 3-way crossover design. The treatments investigating administration of the test preparation in a fasting state, after a standard meal and after a high-caloric fat evening meal, according to commonly applied rules, were shown to be equivalent with respect to the extent of bioavailability (AUC) and the observed maximal concentration (Cmax). Pharmacokinetic parameters describing sustained release characteristics were not changed to any relevant degree. As expected, the co-administration of food resulted in a physiologically determined delay in absorption, which is probably not therapeutically relevant during long-term administration.

Adult↗

PubMed1998

[Absorption profile and absolute bioavailability of a theophylline sustained-release preparation].

In a single-dose crossover study with 16 healthy male nonsmoking volunteers the absorption profile and absolute bioavailability of the sustained release pellets contained in all dosage strengths of Bronchoretard (100, 200, 350, 500 mg anhydrous theophylline) were investigated. One capsule (500 mg theophylline) was given after an evening meal. The reference treatment consisted of an i.v. infusion over 8 h in a total dosage of 350 mg theophylline. Plasma concentration-time profiles were evaluated for 72 h after dosing, respectively start of infusion. Theophylline was measured by high-performance liquid chromatography (HPLC). Absorption profiles (Wagner-Nelson) were derived and the absolute bioavailability was calculated. For the sustained release pellets a liberation/absorption of zero order for 12 h could be noted; the dose-corrected mean absolute bioavailability was 88%. The assumptions of an investigation on absolute bioavailability are discussed and the limitations on generalizability resulting therefrom.

Adolescent↗

PubMed1998

Poly-FISH: a technique of repeated hybridizations that improves cytogenetic analysis of fetal cells in maternal blood.

Prenatal diagnosis of fetal chromosomal abnormalities using interphase fetal nucleated erythrocytes (FNRBCs) separated from maternal peripheral blood can be technically challenging due to the limited number of FNRBCs available for analysis, the limited number of probes that can be used simultaneously, and low FISH efficiency on the formaldehyde-fixed and immunohistochemically stained interphase FNRBCs. We developed a technique of sequential FISH analysis that involves removal of the previous hybridized probe under denaturing conditions, and rehybridization with different probes to improve FISH efficiency. This technique facilitates the analysis of multiple chromosome-specific probes on the same nuclei. Results from our experiments show that FISH can be performed at least nine times on the same interphase nucleus and at least three different probes can be used simultaneously. Thus, theoretically, at least 24 different chromosomes can be analysed on a single interphase fetal cell isolated from maternal blood. We have termed this technique 'Poly-FISH', and have successfully diagnosed trisomy 21, triploidy, and other chromosome abnormalities in FNRBCs using this technique.

Aneuploidy↗

PubMed1998

[Angiodysplasia in a jejunal diverticulum as an unusual cause of lower gastrointestinal bleeding].

Most of intestinal diverticula are found in the jejunum, followed by the terminal ileum. Therefore they can easily be detected either by enteroscopy or ileocolonoscopy. Mostly the patients are asymptomatic so that it is a surprising finding without therapeutic consequences. But if a patient has an unclear enemea or malabsorption problems for which no explanation has been found in upper or lower gastrointestinal endoscopy, it is suggested to do an enteroscopy. We present the case of a 62-year-old woman who presented to our clinic with a first episode of melena. Although she needed blood transfusions no source of bleeding was found in the common diagnostic examinations such as upper and lower endoscopy and X-ray of the intestine. However, in the X-ray and the enteroscopy jejunal diverticula were seen on which angiodysplasias, detected in mesenteric angiography, projected. Because of the impossibility of stopping the bleeding by endoscopic interventions, the patient was referred to surgery and made an uneventful recovery. The hemoglobin done three months later was stabile and the patient was without any symptoms.

Angiodysplasia↗

PubMed1997

Crystal structure of vipoxin at 2.0 A: an example of regulation of a toxic function generated by molecular evolution.

Vipoxin is the main toxic component in the venom of the Bulgarian snake Vipera ammodytes meridionalis, the most toxic snake in Europe. Vipoxin is a complex between a toxic phospholipase A2 (PLA2) and a non-toxic protein inhibitor. The structure is of genetic interest due to the high degree of sequence homology (62%) between the two functionally different components. The structure shows that the formation of the complex in vipoxin is significantly different to that seen in many known structures of phospholipases and contradicts the assumptions made in earlier studies. The modulation of PLA2 activity is of great pharmacological interest, and the present structure will be a model for structure-based drug design.

Amino Acid Sequence↗

PubMed1997

Disease expression in Swiss hereditary non-polyposis colorectal cancer (HNPCC) kindreds.

The genetics of Hereditary Non-Polyposis Colorectal Cancer (HNPCC) has recently been established and found to be associated with DNA mismatch repair deficiency. As the molecular basis of this syndrome does not appear to predict any particular disease, we compared families selected according to the "Amsterdam" criteria (AC) against families that were selected because of an aggregation of colonic and extracolonic malignancies (EC), all of which have been observed in HNPCC families. A comparison of the 2 groups revealed that there were significant differences between them. Age at disease onset for both groups was 20-30 years younger than in the general population; however, a normal age distribution was observed for the AC group whereas for the EC group a bimodal distribution was apparent. The prognosis for both groups together did not differ from that of the general population; however, if split, the AC group had a significantly better outcome than the EC group. Furthermore, dividing the AC group into hMSH2- and hMLH1-linked families revealed that there was no difference in severity of disease between these 2 groups with respect to survival and mean age of disease onset. Both the AC and EC groups displayed a similar tumour spectrum with a virtually identical tumour distribution. A significant finding was the over-representation, of brain tumours in this family set, which comprised the third most common malignancy after endometrial and stomach cancer.

Adult↗

PubMed1997

The human factor H-related protein 4 (FHR-4). A novel short consensus repeat-containing protein is associated with human triglyceride-rich lipoproteins.

A novel apoprotein of an apparent molecular mass of 86 kDa in its unreduced form was identified in human triglyceride-rich lipoproteins. This protein was purified and the amino acid sequence of six proteolytic fragments was found to overlap with that of the factor H-related proteins. In parallel we identified the cDNA encoding a new complement factor H-related protein, termed FHR-4. The sequences of the new apoprotein overlapped with that of the FHR-4 protein. Similar to the previously described factor H-related proteins, FHR-4 contains a hydrophobic signal sequence followed by a stretch of five repetitive elements termed short consensus repeats. Recombinant FHR-4 protein was expressed in the baculovirus system and has an apparent molecular mass of 42 kDa. In addition a 84-kDa dimeric form of the recombinant FHR-4 was detected. Using an immunoaffinity column with antibodies raised against the recombinant FHR-4, we isolated a 86-kDa protein from human plasma. The different molecular mass of the recombinant FHR-4 and the dimeric FHR-4 in plasma is due to different carbohydrate moieties. The 86-kDa plasma protein and the novel apolipoprotein had identical mobility on SDS-polyacrylamide gel electrophoresis analysis and reacted with antisera raised against the reFHR-4 and the purified apoprotein. In conclusion, we have identified a novel factor H-related protein, FHR-4, in human plasma and demonstrate that this protein is present in triglyceride-rich lipoproteins in a dimeric form. This observation provides an intriguing new aspect on possible function(s) of this novel protein and the other factor H-related proteins.

Amino Acid Sequence↗

PubMed1997

Transport of charged dipeptides by the intestinal H+/peptide symporter PepT1 expressed in Xenopus laevis oocytes.

The cloned intestinal peptide transporter is capable of electrogenic H+-coupled cotransport of neutral di- and tripeptides and selected peptide mimetics. Since the mechanism by which PepT1 transports substrates that carry a net negative or positive charge at neutral pH is poorly understood, we determined in Xenopus oocytes expressing PepT1 the characteristics of transport of differently charged glycylpeptides. Transport function of PepT1 was assessed by flux studies employing a radiolabeled dipeptide and by the two-electrode voltage-clamp-technique. Our studies show, that the transporter is capable of translocating all substrates by an electrogenic process that follows Michaelis Menten kinetics. Whereas the apparent K0.5 value of a zwitterionic substrate is only moderately affected by alterations in pH or membrane potential, K0.5 values of charged substrates are strongly dependent on both, pH and membrane potential. Whereas the affinity of the anionic dipeptide increased dramatically by lowering the pH, a cationic substrate shows only a weak affinity for PepT1 at all pH values (5.5-8.0). The driving force for uptake is provided mainly by the inside negative transmembrane electrical potential. In addition, affinity for proton interaction with PepT1 was found to depend on membrane potential and proton binding subsequently affects the substrate affinity. Furthermore, our studies suggest, that uptake of the zwitterionic form of a charged substrate contributes to overall transport and that consequently the stoichiometry of the flux-coupling ratios for peptide: H+/H3O+ cotransport may vary depending on pH.

Animals↗

PubMed1997

Tracer studies with crude U-13C-lipid mixtures. Biosynthesis of the lipase inhibitor lipstatin.

The biosynthesis of the pancreatic lipase inhibitor lipstatin was investigated by fermentation experiments using cultures of Streptomyces toxytricini, which were supplied with soybean oil and a crude mixture of U-13C-lipids obtained from algal biomass cultured with 13CO2. Lipstatin was analyzed by one- and two-dimensional NMR spectroscopy. 13C total correlation spectroscopy and INADEQUATE experiments show that two fatty acid fragments containing 14 and 8 carbon atoms, respectively, are incorporated en bloc into lipstatin. The 14-carbon fragment is preferentially derived from the unsaturated fatty acid fraction, as shown by an experiment with hydrogenated U-13C-lipid mixture, which is conducive to labeling of the 8-carbon moiety but not of the 14-carbon moiety. The data indicate that the lipstatin molecule can be assembled by Claisen condensation of octanoyl-CoA with 3-hydroxy-delta5,8-tetradecanoyl-CoA obtained by beta oxidation of linoleic acid. The formation of lipstatin from acetate units by a polyketide-type pathway is ruled out conclusively by these data. The data show that surprisingly clear labeling patterns can be obtained in studies with crude, universally 13C-labeled precursor mixtures that are proffered together with a large excess of unlabeled material. One- and two-dimensional 13C total correlation spectroscopy analyses are suggested as elegant methods for the delineation of contiguously 13C-labeled biosynthetic blocks.

Enzyme Inhibitors↗

PubMed1997

The Ca2+-inactivated Cl- channel at work: selectivity, blocker kinetics and transport visualization.

Removal of extracellular divalent cations activated a Cl- channel in the plasma membrane of Xenopus laevis oocytes. This so-called Ca2+-inactivated Cl- channel (CaIC) was present in every oocyte and was investigated using two-electrode whole-cell voltage clamp and single-channel patch-clamp techniques. Beside other Cl- channel inhibitors, anthracene-9-carboxylic acid (9-AC) and 3' azido-3'deoxythymidine (AZT), a nucleoside analog we used as an antiviral drug, blocked at least partly the CalC-mediated currents. Using the Cl--sensitive dye 6-methoxy-N-(sulfopropyl)quinolinium (SPQ) we could visualize the transport of Cl- from the oocyte cytoplasm to the surrounding medium after activation of the CaIC by Ca2+ removal. In the absence of external Cl- and Ca2+, the emission intensity of SPQ declined continuously, indicating a quenching of fluorescence by the efflux of Cl- in the millimolar range. In the presence of external Ca2+, no emission changes could be observed during the same time period. Chelating external Ca2+ in absence of Cl- immediately activated Ca2+-inactivated Cl- channels leading to subsequent emission decrease of SPQ. Investigations on the selectivity of the CaIC revealed only poor discrimination between different anions. With single-channel measurements, we found an anion selectivity sequence I- > Br- > Cl- >> gluconate as it is also typical for maxi Cl- channels. Contrary to the majority of all other transport systems of the Xenopus oocyte, which show reduced activity due to membrane depolarization or endocytotic removal of the transport protein from the plasma membrane during oocyte maturation, the CaIC remained active in maturated oocytes. Single-channel measurements on maturated oocytes, also known as eggs, showed the presence of Ca2+-inactivated Cl- channels. However, this egg CaIC revealed an altered sensitivity to external Ca2+ concentrations. All these data confirm and extend our previous observations on the CaIC and give clear evidence that this channel is peculiar among all Cl- channels described up to now.

Animals↗

PubMed1997

Chemical and biological properties of 5-indolones.

Indolones of the general formula 1 (Fig. 1 and 2) can act as Michael substrates, which readily add various nucleophiles. 1,4-Addition of S-nucleophiles to these indolones gives access to compounds of the general formula 2 (Fig. 2). The addition is reversible, meaning that these compounds behave as prodrugs of the (in-vitro) cytotoxic indolones. The addition products possess less cytotoxicity of their own, but can presumably release the parent indolones in-vivo. This behaviour makes them valuable compounds, allowing their use as cytotoxic agents. Furthermore, some of the addition products possess antibiotic activity, making them worth testing as agents against certain microbes. Their specificity towards certain microorganisms, which does not fit the usual scheme of activity towards gram positive or gram negative bacteria, is remarkable and needs further verification.

Animals↗

PubMed1997

Whole-body positron emission tomography in clinical oncology: comparison between attenuation-corrected and uncorrected images.

The clinical need for attenuation correction of whole-body positron emission tomography (PET) images is controversial, especially because of the required increase in imaging time. In this study, regional tracer distribution in attenuation-corrected and uncorrected images was compared in order to delineate the potential advantages of attenuation correction for clinical application. An ECAT EXACT scanner and a protocol including five to seven bed positions, emission scans of 9 min and post-injection transmission scans of 10 min per bed position were used. Uncorrected and attenuation-corrected images were reconstructed by filtered backprojection. In total, 109 areas of focal fluorine-18 fluorodeoxyglucose (FDG) uptake in 34 patients undergoing PET for the staging of malignancies were analysed. To measure focus contrast, a ratio of focus (target) to background average countrates (t/b ratio) was obtained from transaxial slices using a region of interest technique. Calculation of focus diameters by a distance measurement tool and visual determination of focus borders were performed. In addition, images of a body phantom with spheres to simulate focal FDG uptake were acquired. Transmission scans with and without radioactivity in the phantom were used with increasing transmission scanning times (2-30 min). The t/b ratios of the spheres were calculated and compared for the different imaging protocols. In patients, the t/b ratio was significantly higher for uncorrected images than for attenuation-corrected images (5.0+/-3.6 vs 3.1+/-1.4; P<0.001). This effect was independent of focus localization, tissue type and distance to body surface. Compared with the attenuation-corrected images, foci in uncorrected images showed larger diameters in the anterior-posterior dimension (27+/-14 vs 23+/-12 mm; P<0.001) but smaller diameters in the left-right dimension (19+/-11 vs 21+/-11 mm; P<0.001). Phantom data confirmed higher contrast in uncorrected images compared with attenuation-corrected images. It is concluded that, although distortion of foci was demonstrated, uncorrected images provided higher contrast for focal FDG uptake independent of tumour localization. In most clinical situations, the main issue of whole-body PET is pure lesion detection with the highest contrast possible, and not quantification of tracer uptake. The present data suggest that attenuation correction may not be necessary for this purpose.

Female↗

PubMed1997

Cystic fibrosis and non-cystic-fibrosis human nasal epithelium show analogous Na+ absorption and reversible block by phenamil.

Transepithelial short-circuit current (ISC), potential (VT) and resistance (RT) of confluent monolayers of human nasal epithelium cultured from patients with and without cystic fibrosis (CF) were measured. In our Ussing chamber experiments with monolayers derived from non-CF and CF patients neither ISC (non-CF: 14.1 +/- 1.0 microA/cm2, n = 77; CF: 16.7 +/- 1.5 microA/cm2, n = 42), nor RT (non-CF: 288 +/- 15 Omega . cm2; CF: 325 +/- 20 Omega . cm2) showed any significant differences, only VT showed moderate but significant different values (non-CF: -3.6 +/- 0.4 mV; CF: -5.6 +/- 0.7 mV, respectively). Total ISC in CF cells was nearly completely inhibited by amiloride (92 +/- 9.6%), while in non-CF tissue amiloride-insensitive conductances mediated a considerable amount of the ISC (36.3 +/- 6.1%), indicating a lower activity of amiloride-sensitive Na+ conductances in non-CF cells. In both tissues the amiloride-sensitive ISC could also be blocked by the amiloride analogues benzamil, phenamil and 5-(N-ethyl-N-isopropyl)2', 4'-amiloride (EIPA) with different affinities. However, amiloride had a significant lower affinity in CF tissue (half-maximal blocker concentration, K1/2 = 586 +/- 59 nM) compared with non-CF tissue (K1/2 = 294 +/- 22 nM). Astonishingly, phenamil, a blocker which irreversibly blocks all epithelial Na+ channels hitherto described, inhibited the Na+ conductances of human nasal epithelium in a completely reversible way, but nevertheless with high affinity (non-CF: K1/2 = 12.5 +/- 1.2 nM; CF: K1/2 = 17.1 +/- 1.1 nM). Even in high doses none of these blockers had any effect on intracellular Ca2+ concentration as measured with Fura-2. From these findings, we conclude that the epithelial Na+ conductances of human CF nasal epithelium show modified regulation or are functionally different from those of other tissues.

Amiloride↗

PubMed1997

Successful collection of peripheral blood progenitor cells in patients with acute myeloid leukaemia following early consolidation therapy with granulocyte colony-stimulating factor-supported high-dose cytarabine and mitoxantrone.

We evaluated the feasibility of collecting peripheral blood progenitor cells (PBPC) in patients with acute myeloid leukaemia (AML) following two cycles of induction chemotherapy with idarubicin, cytarabine and etoposide (ICE), and one cycle of consolidation therapy with high-dose cytarabine and mitoxantrone (HAM). Thirty-six patients of the multicentre treatment trial AML HD93 were enrolled in this study, and a sufficient number of PBPC was harvested in 30 (83%). Individual peak concentrations of CD34+ cells in the blood varied (range 13.1-291.5/microl; median 20.0/microl). To reach the target quantity of 2.5 x 10(6) CD34+ cells/kg, between one and six (median two) leukaphereses (LP) were performed. The LP products contained between 0.2 x 10(6) and 18.9 x 10(6) CD34+ cells/kg (median 1.2 x 10(6)/kg). Multivariate analysis showed that the white blood cell count prior to HAM and the time interval from the start of HAM therapy to reach an unsupported platelet count > 20 x 10(9)/l were predictive for the peak value of CD34+ cells in the blood during the G-CSF stimulated haematological recovery. In 16 patients an intraindividual comparison was made between bone marrow (BM) and PBPC grafts. Compared to BM grafts, PBPC grafts contained 14-fold more MNC, 5-fold more CD34+ cells and 36-fold more CFU-GM. A CD34+ subset analysis showed that blood-derived CD34+ cells had a more immature phenotype as indicated by a lower mean fluorescence intensity for HLA-DR and CD38. In addition, the proportion of CD34+/Thy-1+ cells tended to be greater in the PBPC grafts. The data indicate that sufficient PBPC can be collected in the majority of patients with AML following intensive double induction and first consolidation therapy with high-dose cytarabine and mitoxantrone.

Acute Disease↗

PubMed1997

Is ADHD a risk factor for psychoactive substance use disorders? Findings from a four-year prospective follow-up study.

OBJECTIVE: To evaluate whether attention-deficit hyperactivity disorder (ADHD) is a risk factor for psychoactive substance use disorders (PSUD), attending to issues of psychiatric comorbidity, family history, and adversity. METHOD: Using assessments from multiple domains, the authors examined 140 ADHD and 120 normal control subjects at baseline and 4 years later. Drug and alcohol abuse and dependence were operationally defined. RESULTS: No differences were detected in the rates of alcohol or drug abuse or dependence or in the rates of abuse of individual substances between the groups; both ADHD and control probands had a 15% rate of PSUD. Conduct and bipolar disorders predicted PSUD, independently of ADHD status. Family history of substance dependence and antisocial disorders was associated with PSUD in controls but less clearly so in ADHD probands. Family history of ADHD was not associated with risk for PSUD. ADHD probands had a significantly shorter time period between the onsets of abuse and dependence compared with controls (1.2 years versus 3 years, p < .01). CONCLUSIONS: Adolescents with and without ADHD had a similar risk for PSUD that was mediated by conduct and bipolar disorder. Since the risk for PSUD has been shown to be elevated in adults with ADHD when compared with controls, a sharp increase in PSUD is to be expected in grown-up ADHD children during the transition from adolescence to adulthood.

Adolescent↗

PubMed1997

A pilot study of neuropsychological function in girls with ADHD.

OBJECTIVE: Attention-deficit hyperactivity disorder (ADHD) is known to have neuropsychological consequences that are evident from psychological tests and from measures of school failure. However, most available data are based on studies of boys. Our goal was to assess, in this pilot study, whether ADHD in girls expressed neuropsychological features similar to those found in boys. METHOD: Subjects were 43 girls, aged 6 to 17 years, with DSM-III-R ADHD and 36 comparison girls without ADHD. Information on neuropsychological performance was obtained in a standardized manner blind to clinical status. RESULTS: Girls with ADHD were significantly more impaired on estimated IQ than comparison girls despite being matched on other demographic variables. Relative to comparison girls, the girls with ADHD were also significantly more impaired on the Freedom From Distractibility subtests of the WISC-R and on arithmetic and reading achievement scores. Although their mean performance on executive function tests was generally poorer than that of control girls, there were no statistically significant differences on these measures. CONCLUSIONS: Girls with ADHD have impairments in some tests of attention and achievement. However, neuropsychological performance on tests of executive function was less impaired than that previously documented in boys with ADHD. If confirmed in a larger sample, these findings suggest that girls with ADHD may be less vulnerable to executive function deficits than boys.

Adolescent↗